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Introduction: Determining ultrafiltration volume in patients undergoing intermittent hemodialysis (IHD) is an essential component in the assessment and management of volume status. Venous excess ultrasound (VExUS) is a novel tool used to quantify the severity of venous congestion at the bedside. Given the high prevalence of pulmonary hypertension in patients with end-stage kidney disease (ESKD), venous Doppler could represent a useful tool to monitor decongestion in these patients. Methods: This is a prospective observational study conducted in ESKD patients who were admitted to the hospital requiring IHD and ultrafiltration. Inferior vena cava maximum diameter (IVCd), portal vein Doppler (PVD), and hepatic vein Doppler (HVD) were performed in all patients before and after a single IHD session. Results: Forty-one patients were included. The prevalence of venous congestion was 88% based on IVCd and 63% based on portal vein pulsatility fraction (PVPF). Both mean IVCd and PVPF displayed a significant improvement after ultrafiltration. The percent decrease in PVPF was significantly larger than the percent decrease in IVCd. HVD alterations did not significantly improve after ultrafiltration. Conclusions: Our study revealed a high prevalence of venous congestion in hospitalized ESKD patients undergoing hemodialysis. After a single IHD session, there was a significant improvement in both IVCd and PVPF. HVD showed no significant improvement with one IHD session. PVPF changes were more sensitive than IVCd changes during volume removal. This study suggests that, due to its rapid response to volume removal, PVD, among the various components of the VExUS grading system, could be more effective in monitoring real-time decongestion in patients undergoing IHD. [ABSTRACT FROM AUTHOR]

Gain-of-function mutations in with no lysine (K)1 (WNK1) and WNK4genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3-Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK's cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values' Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine-rich kinase-[Na.sup.+]-[Cl.sup.-] cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis., Introduction Familial hyperkalemic hypertension (FHHt), also known as Gordon syndrome and pseudohypoaldosteronism type 2, is a rare disease associated with net positive [Na.sup.+] balance and renal [K.sup.+] retention resulting in [...]

Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or the substrate adaptor kelch-like 3 (KLHL3). Disease-associated CUL3 mutations abrogate WNK kinase degradation in cells, but it is not clear how mutant forms of CUL3 promote WNK stability. Here, we demonstrated that an FHHt-causing CUL3 mutant (CUL3 Δ403-459) not only retains the ability to bind and ubiquitylate WNK kinases and KLHL3 in cells, but is also more heavily neddylated and activated than WT CUL3. In cells, activated CUL3 Δ403-459 depleted KLHL3, preventing WNK degradation, despite increased CUL3-mediated WNK ubiquitylation; therefore, CUL3 loss in kidney should phenocopy FHHt in murine models. As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC). Over time, however, Cul3 deletion caused renal dysfunction, including hypochloremic alkalosis, diabetes insipidus, and salt-sensitive hypotension, with depletion of sodium potassium chloride cotransporter 2 and aquaporin 2. Moreover, these animals exhibited renal inflammation, fibrosis, and increased cyclin E. These results indicate that FHHt- associated CUL3 Δ403-459 targets KLHL3 for degradation, thereby preventing WNK degradation, whereas general loss of CUL3 activity - while also impairing WNK degradation - has widespread toxic effects in the kidney., Introduction Familial hyperkalemic hypertension (FHHt; also called pseudo-hypoaldosteronism type II) is a rare monogenic disease characterized by hyperkalemia and hypertension (1). The disease can result from mutations in 4 genes: [...]

The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels. [ABSTRACT FROM AUTHOR]

Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-]i. [ABSTRACT FROM AUTHOR]

Point-of-care ultrasonography (POCUS) has rapidly evolved from a niche technology to an indispensable tool across medical specialties, including nephrology. This evolution is driven by advancements in technology and the visionary efforts of clinicians in emergency medicine and beyond. Recognizing its potential, medical schools are increasingly integrating POCUS into training curricula, emphasizing its role in enhancing diagnostic accuracy and patient care. Despite these advancements, barriers such as limited faculty expertise and 'lack of' standardized guidelines hinder widespread adoption and regulation. The International Alliance for POCUS in Nephrology (IAPN), through this position statement, aims to guide nephrologists in harnessing the diagnostic power of POCUS responsibly and effectively. By outlining core competencies, recommending training modalities and advocating for robust quality assurance measures, we envision a future where POCUS enhances nephrology practice globally, ensuring optimal patient outcomes through informed, evidence-based decision-making. International collaboration and education are essential to overcome current challenges and realize the full potential of POCUS in nephrology and beyond., Competing Interests: S.A. is supported by ECHONous with a research grant in kind. The remainder of the authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Chronic kidney disease (CKD) represents a substantial global burden of disease due to a lack of universal tests and misinterpretation of biomarkers., Objective: To analyze CKD epidemiology in Mexico and guide public policies., Material and Methods: Data from the Global Burden of Disease (GBD) 2021 study were used to describe CKD prevalence and mortality in Mexico for the 1990-2021 period, stratifying by gender and age groups., Results: The prevalence of CKD in Mexico in 2021 was 9,184.9 per 100,000 population. Diabetes was the most common cause of CKD, and CKD-related mortality was high, with an increase in 2019 and 2021, possibly as a consequence of the COVID-19 pandemic., Conclusions: CKD in Mexico entails a high burden of mortality and years of life lost, but it barely contributes to disability. It is essential to improve CKD early detection, access to treatments and coding of the causes of the disease. Moreover, investigating the causes of CKD of unknown etiology, including genetic factors, is crucial in order for specific treatments to be developed in the future., (Copyright: © 2023 Permanyer.)

The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH 2 -terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K + diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K + levels. NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K + and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.